Abstract
Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted.
Highlights
The EGF receptor tyrosine kinase inhibitors (EGFRTKI) gefitinib and erlotinib have shown marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR activating mutations, such as exon 19 deletions and L858R point mutations [1]
E7050 alone did not affect the viability of PC-9/Vec and PC-9/ hepatocyte growth factor (HGF) cells (Fig. 2A–C), E7050 sensitized PC-9/HGF cells to WZ4002 (Fig. 2B and C)
In assessing the effects of HGF overexpression on tumor cell migration, we found that HGF overexpression enhanced the migration activity of PC-9 cells, whereas WZ4002 had no effect against the motility of PC-9/Vec and PC-9/HGF#5 cells
Summary
The EGF receptor tyrosine kinase inhibitors (EGFRTKI) gefitinib and erlotinib have shown marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR activating mutations, such as exon 19 deletions and L858R point mutations [1]. Acquire resistance to EGFR-TKIs after varying periods of time. Among the molecular mechanisms of this acquired resistance to EGFR-TKIs are gatekeeper mutations in EGFR (i.e., a T790M second mutation) and bypass. PIK3CA mutations and transformation to SCLC have been found to contribute to EGFR-TKI resistance in a subpopulation of tumors [6]. All of these alterations have been detected in clinical specimens from patients with EGFR mutant lung cancer who became resistant to EGFR-TKIs [6, 7], indicating the urgent need to develop effective therapies for these patients
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